Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenv...Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment(TME)and systemic toxicity caused by excessive cytokine release.As a key regulator of the immunosuppressive TME,TGF-βpromotes cytokine synthesis via the NF-κB pathway.Here,we coexpressed SMAD7,a suppressor of TGF-βsignaling,with a HER2-targeted CAR in engineered T cells.These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-β-triggered exhaustion,which enabled sustained tumoricidal capacity after continuous antigen exposure.Moreover,SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells.Mechanistically,SMAD7 downregulated TGF-βreceptor I and abrogated the interplay between the TGF-βand NF-κB pathways in CAR-T cells.As a result,these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-β.SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids.Therefore,our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.展开更多
The combination of the immunotherapy(i.e.,the use of monoclonal antibodies)and the conventional chemotherapy increases the long-term survival of patients with lymphoma.However,for patients with relapsed or treatment-r...The combination of the immunotherapy(i.e.,the use of monoclonal antibodies)and the conventional chemotherapy increases the long-term survival of patients with lymphoma.However,for patients with relapsed or treatment-resistant lymphoma,a novel treatment approach is urgently needed.Chimeric antigen receptor T(CAR-T)cells were introduced as a treatment for these patients.Based on recent clinical data,approximately 50%of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy.Moreover,clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy.Other than the CD19-targeted CAR-T,the novel target antigens,such as CD20,CD22,CD30,and CD37,which were greatly expressed on lymphoma cells,were studied under preclinical and clinical evaluations for use in the treatment of lymphoma.Nonetheless,the CAR-T therapy was usually associated with potentially lethal adverse effects,such as the cytokine release syndrome and the neurotoxicity.Therefore,optimizing the structure of CAR,creating new drugs,and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.展开更多
1文献来源Adusumilli PS,Zauderer MG,Rivière I,et al.A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease,in combination with the anti-PD-1 agent pembrolizum...1文献来源Adusumilli PS,Zauderer MG,Rivière I,et al.A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease,in combination with the anti-PD-1 agent pembrolizumab[J].Cancer Discov,2021,11(11):2748-2763.2证据水平1b。展开更多
The efficacy and specificity of conventional monoclonal antibody(mAb)drugs in the clinic require further improvement.Currently,the development and application of novel antibody formats for improving cancer immunothera...The efficacy and specificity of conventional monoclonal antibody(mAb)drugs in the clinic require further improvement.Currently,the development and application of novel antibody formats for improving cancer immunotherapy have attracted much attention.Variable region-retaining antibody fragments,such as antigen-binding fragment(Fab),single-chain variable fragment(scFv),bispecific antibody,and bi/trispecific cell engagers,are engineered with humanization,multivalent antibody construction,affinity optimization and antibody masking for targeting tumor cells and killer cells to improve antibody-based therapy potency,efficacy and specificity.In this review,we summarize the application of antibody variable region engineering and discuss the future direction of antibody engineering for improving cancer therapies.展开更多
基金supported by a grant from the National Natural Science Foundation of China(No.81972870)the Independent Research Topic of State Key Laboratory of Cancer Biology of Fourth Military Medical University(CBSKL2022ZZ20)+2 种基金Shaanxi Innovative Research Team for Key Science and Technology(S2022-ZC-TD-0065)the Natural Science Foundation of Henan Province(No.222300420264)Tangdu Hospital-key research project(2022TDGS007).
文摘Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment(TME)and systemic toxicity caused by excessive cytokine release.As a key regulator of the immunosuppressive TME,TGF-βpromotes cytokine synthesis via the NF-κB pathway.Here,we coexpressed SMAD7,a suppressor of TGF-βsignaling,with a HER2-targeted CAR in engineered T cells.These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-β-triggered exhaustion,which enabled sustained tumoricidal capacity after continuous antigen exposure.Moreover,SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells.Mechanistically,SMAD7 downregulated TGF-βreceptor I and abrogated the interplay between the TGF-βand NF-κB pathways in CAR-T cells.As a result,these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-β.SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids.Therefore,our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.81230014,81470341,81520108002,and 81500157)the Key Project of Science and Technology Department of Zhejiang Province(No.2018C03016-2)the Key Research and Development Program of Zhejiang Province(No.2019C03016).
文摘The combination of the immunotherapy(i.e.,the use of monoclonal antibodies)and the conventional chemotherapy increases the long-term survival of patients with lymphoma.However,for patients with relapsed or treatment-resistant lymphoma,a novel treatment approach is urgently needed.Chimeric antigen receptor T(CAR-T)cells were introduced as a treatment for these patients.Based on recent clinical data,approximately 50%of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy.Moreover,clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy.Other than the CD19-targeted CAR-T,the novel target antigens,such as CD20,CD22,CD30,and CD37,which were greatly expressed on lymphoma cells,were studied under preclinical and clinical evaluations for use in the treatment of lymphoma.Nonetheless,the CAR-T therapy was usually associated with potentially lethal adverse effects,such as the cytokine release syndrome and the neurotoxicity.Therefore,optimizing the structure of CAR,creating new drugs,and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.
文摘1文献来源Adusumilli PS,Zauderer MG,Rivière I,et al.A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease,in combination with the anti-PD-1 agent pembrolizumab[J].Cancer Discov,2021,11(11):2748-2763.2证据水平1b。
基金CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-017。
文摘The efficacy and specificity of conventional monoclonal antibody(mAb)drugs in the clinic require further improvement.Currently,the development and application of novel antibody formats for improving cancer immunotherapy have attracted much attention.Variable region-retaining antibody fragments,such as antigen-binding fragment(Fab),single-chain variable fragment(scFv),bispecific antibody,and bi/trispecific cell engagers,are engineered with humanization,multivalent antibody construction,affinity optimization and antibody masking for targeting tumor cells and killer cells to improve antibody-based therapy potency,efficacy and specificity.In this review,we summarize the application of antibody variable region engineering and discuss the future direction of antibody engineering for improving cancer therapies.
